Method and apparatus for sterile or aseptic handling of containers

ABSTRACT

The invention relates to a device and a method for the sterile or aseptic handing of containers, which method includes at least the following process step of: evaluating whether a container is safely closed by means of a stopper by determining whether an expected low pressure, preferably a vacuum, is present in the interior of the container.

PRIOR ART

The invention is based on a method and an apparatus for sterile oraseptic handling of containers as generically defined by the preamblesto the independent claims. From European Patent Disclosure EP 1 447 328B1, a method for sterile metering of vials is already known. After thevial and cap have been put together, they are rinsed. Next, a protectoris placed thereon. In an autoclave, the arrangement is sterilized. Aftercooling and removal of the protector and cap, the liquid is dispensedinto the vial. Next, the vial is closed again. The filling is recordedwith a video camera for purposes of documentation. After theencapsulation, the vial is provided, by means of a laser beam, withidentification that says when the metering was done.

It is the object of the present invention to reduce the number ofhandling steps, especially in the time prior to the filling operation.This object is attained by the characteristics of the independentclaims.

Advantages of the Invention

Methods and apparatuses according to the invention for sterile handlingof containers are distinguished in that it is checked whether acontainer is safely closed with a stopper by ascertaining whether anexpected underpressure, preferably a vacuum, is still present in theinterior of the container. Thus the combination of the container closedwith a stopper is sterilized and also delivered in this combination forfilling. This avoids having to deliver the stoppers for closureseparately along with the necessary sterilization processes. Moreover,the check for integrity ensures that the delivered containers withstoppers meet the sterility requirements, since the containers areproperly closed, and in every case the interior thereof still meets thesterility requirements. This concept also makes it possible for thestopper, which is to be removed in the filling process, to be used,preferably by the same handling device, for closure after the fillinghas been done. A device for supplying stoppers separately can also bedispensed with. Preferably, the manipulator, such as a gripper device,which must be provided in any case for stopper removal, is used forclosing the filled container as well. As a result, the costs for thesystem can be reduced still further.

In an expedient refinement, it is provided that the checking of theexpected underpressure is effected on the basis of a force measurementof that particular force that is necessary for removing the stopper fromthe container. A corresponding force-measuring device can be provided,or is already present, on the stopper removal device, such as amanipulator. The force is a measure for whether the interior of thecontainer is still subjected to the expected underpressure, which allowsthe conclusion to be drawn that the container and stopper arrangement issafe. If underpressure is still present, the force that must be exertedto remove the stopper is significantly greater than would be the casewith a damaged container and stopper connection with an associatedpressure equilibrium in the interior. Thus the force is a good indicatorof the integrity of the arrangement of the container with the stopper.Since the manipulator, to remove the stopper, must necessarily come intomechanical contact with the stopper anyway, force measurement is alsoeasy to achieve.

In an expedient refinement, it is provided that the checking of theexpected underpressure is effected optically. To that end, a laser beamis preferably shone through the container. On the basis of the opticalspectrum of the radiation arriving on the other side, conclusions can bedrawn about the medium located in the container or about pressureconditions in the interior of the container. In the case ofunderpressure, an altered spectrum must be expected, compared to whatwould be the case at ambient pressure, or in other words in thesituation where a stopper is no longer properly seated. Such opticalchecking devices can be installed without major additional expense andare known in principle.

In an expedient refinement, it is provided that a plurality of closedcontainers are placed in at least one tray. The containers located inthe tray, closed with stoppers and with an underpressure applied in theinterior, are subsequently sterilized. The sterilization can be done forinstance by the manufacturer of the containers and stoppers. However, itwould also be conceivable to do the sterilization directly beforefilling. Handling by means of trays simplifies the transporting anddelivery of the containers to downstream process steps.

In an expedient refinement, it is provided that the checking whether thecontainer is safely closed with a stopper is done under clean roomconditions. It can thus be ensured that when the stopper is removed forchecking or for ensuing filling of the container, re-sterilization ofthe container need no longer be done. As a result, the number ofrequired steps for sterilizing the containers is reduced.

Further expedient refinements will become apparent from furtherdependent claims and from the specification.

DRAWINGS

One exemplary embodiment of the method and of the apparatus for sterilehandling of containers is shown in the drawings and will be described infurther detail below.

FIG. 1 schematically shows the three process steps, from closing thecontainers to their sterilization;

FIG. 2 shows the process steps, from checking whether the container issafely closed with a stopper to the closure of the filled containers;

FIG. 3 shows the checking of the underpressure by means of opticalmethods;

FIG. 4 shows the checking of the underpressure by means of mechanicalforce measurement; and

FIG. 5 shows a bar gripper for the removal or placement of a pluralityof stoppers.

In a vacuum chamber 14, a stopper 12 is placed on a container 10 by astopper closure device 16 and closed with the application of anunderpressure. Thus an underpressure is created in the interior of thecontainer 10 as well. The containers 10 thus closed at underpressure,preferably a vacuum, are then placed in trays 18 by a gripper device 19,so that now a plurality of containers 10, closed with stoppers 12, arepositioned in a tray 18. This tray 18, with the containers 10 disposedin it, proceeds into a sterilizer 12, in which the containers 10 aresterilized. Next, the trays 18 are provided with a surrounding packagingas protection during shipping.

The thus-sterilized containers 10 are then brought into a clean room 22,in which a plurality of stations are disposed. One of these is a testingunit 24. This unit 24 checks whether the expected underpressure prevailsin the interior of the still-closed container 10, as an indicator for anintact container that is still properly closed with the stopper 12. Aspart of a stopper removal device 26, a suitable manipulator or gripperdevice 44 removes the stopper 12. Next, the opened container 10—if itwas recognized as being properly closed—is filled in a filling machine28. Optionally, filled containers 10 can be subjected to an internalprocess control 30, which ascertains whether the container 10 has beenfilled with the correct quantity of liquid. In a closing station 32,which can also be a component of the filling machine 28, the filledcontainer 10 is re-closed with the stopper 12.

In FIG. 3, the checking is done as to whether the container is safelyclosed with a stopper. To that end, a laser 36 shines through thepreferably transparent container 10. The radiation passing through thecontainer 10 is detected on the other side by an optical receiver 38.The properties of the detected radiation provide information as towhether an expected underpressure still prevails in the interior of thecontainer 10. It can thus be told whether the container 10 is stillsafely closed with the stopper 12.

In an alternative embodiment of the testing unit 24, a gripper device 44is now provided with a gripper 42, which serves to remove the stopper 12from the container 10. The gripper device 44 is furthermore providedwith a force-measuring device 46, which ascertains a measure for thepressure required for removing the stopper 12. From the pressuredetected, it is recognized whether the expected underpressure stillprevails in the interior of the container 10, or whether the container10 is no longer properly closed. Upon the application of anunderpressure or vacuum in the interior of the container 10, asignificantly greater force is required for removing the stopper 12,which thus provides information as to the safeness of the closure of thecontainer 10 with the stopper 12. The container 10 is provided on itsunderside with a flange 40, which cooperates with a retaining device,not shown, for exerting a contrary force for removing the stopper 12.

FIG. 5 shows the top view on a bar gripper 48 that has a plurality ofopenings for receiving a plurality of stoppers 12.

The devices shown in the drawings function as follows: The containers 10are filled, preferably in the pharmaceutical field with medications,under aseptic conditions and then re-closed with the stoppers 12. Thecontainers 10 may for instance be vials or bottles made of glass orplastic, or the like. The liquid pharmaceuticals dispensed into thecontainers 10 are removed in the hospital or the doctor's office, forinstance by piercing the stopper 12 with an injection needle. Thestopper 12 is equipped accordingly for that purpose.

To reduce the number of sterilization steps in the time before thefilling of the containers 10, it is now proposed that in a first step,the container 10 and the stopper 12 are closed. This can be done forinstance at the manufacturer of the containers 10 and/or stoppers 12. Inthe ensuing sterilization step, in order to tell reliably that thecontainer 10 is still properly closed by the stopper 12 and that theclosure is intact before further processing, an underpressure,preferably a vacuum, is generated in the interior of the container 10.This is done in the vacuum chamber 14, in which the container 10 isclosed with a stopper 12 by means of the stopper closure device 16. Thestopper closure device 16 may for instance be a manipulator, that is, arobot with a gripper. Under some circumstances, it could be providedthat a protector be disposed over the stopper 12, which protects thestopper 12 for the further handling processes. However, this protectoris not absolutely necessary.

In a further step, the various closed containers 10 are delivered by thegripper device 19 to a tray 18. The tray 18 has receptacles and openingsthat are adapted to the outer diameter of the container 10, so that aplurality of these containers 10 can be received in the tray 18 and thuscan be delivered simultaneously to the further processing operations.Although this so-called preformatting is helpful for further handling,it is not absolutely necessary.

The tray 18 thus equipped with containers 10 is now delivered to asterilizer 20. The underpressure or vacuum continues to exist in theinterior of the containers 10, as long as the closures remain safe; thatis, as long as the stopper 12 correctly closes the container 10 so thatthe underpressure cannot escape. The sterilizer 20 employs conventionalsterilizing methods, based for instance on radiation sterilization (forinstance with gamma rays), heat generation, for instance by means ofplasma, or electron beams, or the like. The sterilizer 20 could beeffected either inline, that is, in the context of the filling processand thus in the vicinity of the filling machine 28. However, thesterilizer 20 could equally be located spatially separately from thefilling machine 28, for instance at specialized companies that performthe sterilization of the container 10 with the stopper 12 placed on itusing underpressure prevailing in the interior of the container. Bymeans of the sterilization process, the interior of the container 10 issterilized as well. In the case of a sterilizer 20 located remotely fromthe filling machine 28, the tray 18 could be packaged accordingly forbeing transported to the filling machine 28 under sterile conditions.

Once the sterilization has been done, the closed containers 10 enter theclean room 22. Before that, any packaging that may have been presentaround the containers 10 or the trays 18 is removed. Containers 10disposed on the tray 18 could also be separated again. Alternatively,the containers 10 could be delivered to the clean room 22 while stilldisposed on the tray 18.

The testing unit 24 is located in the clean room 22. However, it couldalso be disposed in a separate clean room that is separate from that ofthe filling machine 28. The testing unit 24 ascertains whether thestopper 12 is still properly closing the container 10. This isascertained from indicators of the pressure conditions in the interiorof the container 10. If the stopper 12 is still properly closing thecontainer 10, then an underpressure or vacuum still prevails in theinterior. However, in the event of a defect, the interior as well willbe exposed to ambient pressure. Different versions of the testing unit24 will be described hereinafter in conjunction with FIGS. 3 and 4.Containers 10 in which an expected underpressure does not prevail in theinterior are removed and not filled, since they do not meet thesterility requirements.

In the case of containers 10 that are intact—the expected underpressurestill prevails in the interior—the various stoppers 12 are removed. Thiscan be done for instance by means of the gripper device 44 that is alsodisposed in the clean room 22. The opened container 10 is now filledwith the desired quantity of the desired liquid in the desired quantityin the filling machine. In an internal process control 30, the desiredfilling quantity is monitored, and if deviations occur, correctiveprocedures are initiated. To that end, the weight or the fill level ofthe filled container 10 is for instance ascertained, for instance bymeans of X-radiation or optically.

Next, in the closing station 32, the corresponding stopper 12 is placedback on the filled container 10. For that purpose, the same gripperdevice 44 could preferably hold the removed stopper 12 during thefilling operation and then place it back on again in the context of theclosure operation. This would eliminate a separate stopper delivery. Apick-and-place device could be provided as the gripper device 44. Beforeclosure with the stopper 12, freeze drying might possibly be necessary,to remove condensate from the container 10.

Next, the closed container 10 is transported onward to a cap placementstation, which places a cap as well on the container 10 that is closedwith the stopper 12 and connects the cap to the container 10, forinstance by means of crimping. Suitable marking of the container 10 withregard to production information or the like, for instance by means oflasers, can then ensue as well.

The testing unit 24 can employ arbitrary physical principles, which aresuitable for performing underpressure detection or vacuum detection inthe interior of the container 10. For example, optical methods aresuitable, if a laser 36 shines through the interior of the container 10.The arriving radiation is detected by a receiver 38. From the frequencyspectrum, it can for instance be found whether a vacuum prevails in theinterior of the container 10, or not. For instance, the opticalabsorption behavior in a vacuum is different from what it is at ambientpressure. It would also be possible to dispose the receiver 38 on thesame side as the laser 36 and to divert the radiation that passesthrough the interior to the receiver 38 by means of a reflector.

Another advantageous embodiment of the testing unit 24 is shown in FIG.4. For filling the container 10, the stopper 12 must be removed anyway.This is done by the gripper device 44. This gripper device 44 can now beadditionally equipped with a force-measuring device 46, or theforce-measuring device is present anyway in the case of a robot arm.Based on the force that is necessary for removing the stopper 12 fromthe container 10, conclusions can be drawn about the pressure conditionsthat prevail in the interior of the container 10. For instance, asignificantly increased expenditure of force is necessary to remove thestopper 12 from the container 10 in the presence of underpressure orvacuum than is the case with ambient pressure. The detected force iscompared with a limit value. If the force is below the limit value, thisis an indication of a container 10 that is no longer intact, since giventhe force detected, everything points to a broken vacuum.

To facilitate the removal of the stopper 12, the container 10 isprovided on its lower edge with a securing flange 40 annularlysurrounding that edge. The upper side of the securing flange 40 issurrounded by a fixed retaining device 50, so that the container 10 uponremoval of the stopper 12 cannot be moved upward as well along with thestopper. The gripper device 44 may also be embodied as a bar gripper 48.Then it becomes possible to remove a plurality of stoppers 12simultaneously from the respective containers 10. Gripper devices 44 orbar grippers 48 can be used on the stopper removal devices 26. They canalso be positioned in such a way that after filling of the containers 10has been done, the removed stoppers 12 are plated back on the containers10 in the closing station 32. Thanks to this multifunctionality of thegripper devices, the overall construction of the system can besimplified still further.

Methods and apparatuses for sterile handling of containers are suitableparticularly for filling machines involving liquid or pourable bulkgoods that are subject to special sterility requirements. This isparticularly the case in the pharmaceutical industry or in the case offoods. However, the use of methods and apparatuses for sterile handlingof containers is not limited to those fields of use.

1-11. (canceled)
 12. A method for sterile or aseptic handling ofcontainers, including at least the following step: before filling atleast one container, checking whether the container is safely closedwith a stopper by ascertaining whether an expected underpressure,preferably a vacuum, is present in an interior of the container.
 13. Themethod as defined by claim 12, wherein the step of checking byascertaining of the expected underpressure is effected on a basis of aforce measurement of the force that is necessary for removing thestopper from the container.
 14. The method as defined by claim 12,wherein the step of checking by ascertaining of the expectedunderpressure is effected optically.
 15. The method as defined by claim12, wherein after the step of checking whether the container is safelyclosed with stopper, the stopper is removed; the container is filled;and the container is then closed with the removed stopper or anotherstopper.
 16. The method as defined by claim 13, wherein after the stepof checking whether the container is safely closed with stopper, thestopper is removed; the container is filled; and the container is thenclosed with the removed stopper or another stopper.
 17. The method asdefined by claim 14, wherein after the step of checking whether thecontainer is safely closed with stopper, the stopper is removed; thecontainer is filled; and the container is then closed with the removedstopper or another stopper.
 18. The method as defined by claim 15,wherein before the step of checking whether the container is safelyclosed with a stopper is done, the container is closed by the stopper,with a generation of an underpressure, preferably a vacuum, in aninterior of the container.
 19. The method as defined by claim 16,wherein before the step of checking whether the container is safelyclosed with a stopper is done, the container is closed by the stopper,with a generation of an underpressure, preferably a vacuum, in aninterior of the container.
 20. The method as defined by claim 17,wherein before the step of checking whether the container is safelyclosed with a stopper is done, the container is closed by the stopper,with a generation of an underpressure, preferably a vacuum, in aninterior of the container.
 21. The method as defined by claim 18,wherein after the container is closed by the stopper and the generationof an underpressure or a vacuum in the interior of the container, theclosed container is sterilized.
 22. The method as defined by claim 19,wherein after the container is closed by the stopper and the generationof an underpressure or a vacuum in the interior of the container, theclosed container is sterilized.
 23. The method as defined by claim 20,wherein after the container is closed by the stopper and the generationof an underpressure or a vacuum in the interior of the container, theclosed container is sterilized.
 24. The method as defined by claim 12,wherein the step of checking whether the container is safely closed witha stopper is done under clean room conditions.
 25. The method as definedby claim 23, wherein the step of checking whether the container issafely closed with a stopper is done under clean room conditions.
 26. Anapparatus for sterile or aseptic handling of containers, including atesting unit for checking a container as to whether it is safely closedwith a stopper, the testing unit ascertaining whether an expectedunderpressure, preferably a vacuum, is present in an interior of thecontainer.
 27. The apparatus as defined by claim 26, wherein the testingunit includes an optical signal transducer with a receiver whichtogether check whether an expected underpressure, preferably a vacuum,is present in the interior of the container.
 28. The apparatus asdefined by claim 26, wherein the testing unit includes a force-measuringdevice, which ascertains the force which is necessary for removing thestopper from the container, in order to ascertain whether an expectedunderpressure, preferably a vacuum, is present in the interior of thecontainer.
 29. The apparatus as defined by claim 26, wherein a gripperdevice is provided, which before the containers are filled, removes thestopper and sets the stopper back onto the container after the containeris filled.
 30. The apparatus as defined by claim 27, wherein a gripperdevice is provided, which before the containers are filled, removes thestopper and sets the stopper back onto the container after the containeris filled.
 31. The apparatus as defined by claim 28, wherein a gripperdevice is provided, which before the containers are filled, removes thestopper and sets the stopper back onto the container after the containeris filled.